The present invention relates to fluoro-substituted adamantane derivatives that are metabolically more stable than the corresponding adamantane derivatives that are not fluoro-substituted. To enhance the metabolic stability of a pharmaceutical compound that includes an adamantane moiety, in accord with the present invention a fluoro-substituted adamantane moiety may be introduced in the pharmaceutically active compound in place of the non-fluorinated adamantane moiety. The fluoro-substituted adamantane derivatives of the present invention may also be used as pharmaceutical compounds for the treatment or prevention of memory loss, or for the treatment of Parkinson's disease or viral infections.
The addition of an adamantane moiety to the chemical structure of a pharmaceutical compound is a recognized method of enhancing the absorption of the compound in the central nervous system (CNS) of a patient. J. Pharmaceutical Sciences 83, 481 (1994). Since this property may be beneficial for pharmaceutical compounds directed to the CNS, efforts have been made to modify existing drugs to include the adamantane functionality. Biochem. Pharmacol. 41(4), R5-R8 (1991). Several adamantane-containing pharmaceutical compounds have been developed, including the following: amantadine hydrochloride (antiviral agent; treatment of Parkinson's disease), tromantadine (antiviral agent), amantol (antifungal; antibacterial agent), adatanserin (anxiolytic agent), rimantadine (antiviral agent), memantine (memory enhancement agent), somantadine (antiviral agent), and adapalene (antiacne agent). The adamantane moiety is lipophilic, which facilitates the tissue distribution of a drug containing the moiety, but the lipophilic nature of the adamantane group may also facilitate the metabolic degradation of the adamantane group through oxidation. In accord with the present invention, it has been found that by fluorinating one or more of the bridge-head carbons of the adamantane group, the metabolic stability of the adamantane group is enhanced without affecting the lipophilicity of the group.